A mouse model for SPG48 reveals a block of autophagic flux upon disruption of adaptor protein complex five

Neurobiology of Disease

Federico Ribaudo¹  Muhammad Awais Afzal²  Eva-Maria Piskor³  Markus Damme³  Christian A. Hübner⁴  Melanie Thelen⁵  Dominic Winter⁶  Birgit Hoffmann⁶  Patricia Franzka⁷  Christian Kosan⁷  Tassula Proikas-Cezanne⁸  Tobias Stauber⁹  Judith Klumperman⁹  Adeela Hussain^1,10  Tanja Hermann^1,10  Cecilia de Heus^1,10  Mukhran Khundadze^1,10  Lisa von Kleist^1,10  Jan Rosentreter^1,10  Sandor Nietzsche^1,10 

[1] Corresponding author at: Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University Jena, Am Klinikum 1, Jena 07747, Germany.;Biomolecular Photonics Group, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07743, Germany;Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584, Netherlands;Department of Molecular Biology, Eberhard Karls University Tübingen, Tübingen 72076, Germany;Electron Microscopy Center, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07743, Germany;Institute for Biochemistry and Molecular Biology, University of Bonn, Bonn 53115, Germany;Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Jena 07743, Germany;Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel 24118, Germany;Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany;Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07747, Germany;

关键词: AP5;    ALR;    Autophagy;    Lysosome;    SPG48;   

DOI  :  

来源: DOAJ

【 摘 要 】

Hereditary spastic paraplegia is a spastic gait disorder that arises from degeneration of corticospinal axons. The subtype SPG48 is associated with mutations in the zeta subunit of the adaptor protein complex five (AP5). AP5 function and the pathophysiology of SPG48 are only poorly understood. Here, we report an AP5 zeta knockout mouse, which shows an age-dependent degeneration of corticospinal axons. Our analysis of knockout fibroblasts supports a trafficking defect from late endosomes to the transGolgi network and reveals a structural defect of the Golgi. We further show that both autophagic flux and the recycling of lysosomes from autolysosomes were impaired in knockout cells. In vivo, we observe an increase of autophagosomes and autolysosomes and, at later stages, the accumulation of intracellular waste in neurons. Taken together, we propose that loss of AP5 function blocks autophagy and thus leads to the aberrant accumulation of autophagic cargo, which finally results in axon degeneration.

【 授权许可】

Unknown